HAE Drug Data See Peer-Reviewed Light of Day

Action Points

Explain to interested patients that these studies suggest that there are now several treatments and one preventive therapy for hereditary angioedema, but further work is needed to compare the three treatments and understand advantages and disadvantages for the use of each.

Results of phase III trials of two approved drugs for hereditary angioedema (HAE) and another in the late-stage pipeline have finally emerged from the gauntlet of peer review.

Reports on a pasteurized and nanofiltered form of human C1 esterase inhibitor (Cinryze) and the synthetic agents ecallantide (Kalbitor) and icatibant (Firazyr) -- the latter still in development -- appeared in the Aug. 4 issue of the New England Journal of Medicine.

Much of the data in all three papers had already been reported at meetings in 2008 and 2009, but this is the first publication of full reports in a peer-reviewed journal.

HAE, a rare disorder, is the result of a genetic defect in a regulatory protein that keeps C1 complement in check. Patients suffer frequent, unpredictable attacks marked by swelling and acute pain in various parts of the body.

The C1 esterase inhibitor Cinryze, as well as a similar agent (Berinert) already FDA approved for acute attacks, are straight replacement products, derived from human plasma and treated to eliminate viral contaminants. The synthetic drugs come at HAE a different way, targeting bradykinin activity to block the downstream inflammatory effects of overactive complement.

Aleena Banerji, MD, of Massachusetts General Hospital in Boston, and colleagues reported data from two phase III trials of icatibant, FAST-1 and FAST-2. The results explain why the FDA in 2008 rejected a marketing application submitted by its manufacturer, the German firm Jerini AG.

Paradoxically, the placebo-controlled FAST-1 trial failed to meet its primary endpoint, a significant reduction in median time to clinically significant relief of acute HAE attacks, whereas FAST-2 did show a significant advantage versus an active comparator.

In the 56-patient FAST-1 study, the median time to meaningful symptom relief was 2.5 hours compared with 4.6 hours in the placebo group (P=0.14).

In FAST-2, a similar effect was seen for icatibant, but patients receiving the active comparator, tranexamic acid, had far worse outcomes than the placebo patients in FAST-1. Median response times in FAST-2 were 2.0 hours for icatibant versus 12.0 hours with tranexamic acid (P<0.001).

Differences between the two studies in the use of rescue medications likely accounted for the different outcomes, Banerji and colleagues indicated, not any action of tranexamic acid.

Nearly half the placebo group in FAST-1 required rescue medication with C1 esterase inhibitor or other treatments because of inadequate relief or worsening symptoms. In FAST-2, on the other hand, only about 20% of patients assigned to tranexamic acid received rescue medications.

Data from patients receiving rescue medication were not censored. Also, the primary endpoint in FAST-1 was judged only for the "index symptom," the patient's primary complaint at the start of treatment, and not for other symptoms.

This "stringent definition" of the primary endpoint and inclusion of placebo patients who received early rescue medication explained the relatively small difference in outcomes in FAST-1, Banerji and colleagues concluded.

Nevertheless, Jerini is now sponsoring another trial, FAST-3, in hopes of allaying the FDA's doubts about the drug's efficacy.

Ecallantide Report Has No Mention of Anaphylaxis

The ecallantide report, from Marco Cicardi, MD, of the University of Milan, and colleagues, covered the drug's 72-patient, placebo-controlled pivotal trial called EDEMA3 in patients with acute attacks.

Median time to significant improvement -- defined as the patient's first report that overall symptoms were "a lot better or resolved" -- was 2.75 hours with ecallantide compared with more than four hours for placebo.

That was not the study's primary endpoint, however, which was a so-called treatment outcome score at four hours after treatment. Scores could range from -100 to +100, reflecting significant worsening or significant improvement, respectively.

The mean four-hour score was 46.8 (SD 59.3) with ecallantide versus 21.3 (SD 69) in the placebo group (P=0.004), Cicardi and colleagues reported.

The report sidestepped mention of hypersensitivity or anaphylactic reactions that have previously been reported with the drug. Cicardi and colleagues indicated that no such reactions occurred in EDEMA3.

But a total of 16 such reactions had been seen in other trials, leading the FDA to require a boxed warning indicating that the drug should be administered by health professionals prepared to manage serious reactions.

The problem has dashed hopes, at least for the present, that patients could carry ecallantide self-injectors to treat acute HAE attacks themselves.

Cinryze Looking for Acute Tx Indication

The piece of the NEJM package included a report from Bruce Zuraw, MD, of the University of California San Diego, and colleagues on the nanofiltered C1 esterase inhibitor Cinryze. It covered two studies, a 68-patient placebo-controlled trial of the drug as a treatment for acute attacks, and a 22-patient study of twice-weekly Cinryze treatments for preventing attacks.

Cinryze won FDA approval in October 2008 for preventing HAE attacks, and the NEJM report includes data from a trial for that purpose. But its manufacturer is also seeking approval for the drug as a treatment for acute attacks; data from a study intended to support that indication were also included in the NEJM paper

The acute-attack trial had time to "unequivocal" symptom relief as its primary outcome. The median was 2.0 hours for Cinryze versus more than 4.0 hours for placebo (P=0.02), according to Zuraw and colleagues.

On the other hand, 40% of Cinryze patients failed to achieve unequivocal relief within four hours, the researchers indicated, a lower success rate than seen in earlier studies.

Zuraw and colleagues also reported that open-label treatment resulted in improvement 93% of the time. They suggested this finding might be a better representation of real-life clinical responses, as "fear of receiving placebo" would not be a factor.

Nevertheless, the FDA last year told the drug's manufacturer, ViroPharma, that another acute-treatment trial would be needed before approval for an acute-treatment indication would be granted. The agency indicated that the existing data "lacked robustness," according to the company.

Berinert was approved last year as a treatment for acute attacks, but Cinryze is currently the only drug approved for preventing them.

The prophylaxis trial, which used a placebo-controlled crossover design, found that only two of the 22 patients had more HAE attacks during the 12-week active-treatment period relative to a 12-week placebo period.

The mean number of attacks in the Cinryze group was 6.26, compared with 12.73 for placebo (P<0.001).

Choosing One Agent Over Another

An accompanying editorial by B. Paul Morgan, MB, PhD, of Cardiff University in Wales, noted that clinicians now need studies to help them sort through the trade-offs involved with using one of these agents versus another.

Noting that C1 esterase inhibitors have been marketed in Europe for many years, he wrote that this class "has proved to be safe and effective during decades of use."

But the other agents have advantages as well, he pointed out. "Newer agents eliminate the perceived risk of infection; some provide additional target specificity," Morgan wrote.

"Head-to-head comparisons are needed to guide the choice of agents for the treatment of acute attacks and prophylaxis," according to Morgan. "Practical matters, particularly the stability of the drug and the route of administration, are likely to be critical, because optimal therapy requires prompt self-administration at the first hint of an attack."

The C1 esterase inhibitor study was funded by Lev Pharmaceuticals, now owned by ViroPharma Biologics.

The ecallantide study was funded by Dyax.

The icatibant studies were funded by Jerini AG, now part of Shire, with partial National Institutes of Health support for FAST-1.

Zuraw reported consulting relationships with Lev, CSL Behring, Jerini, and Dyax; travel expenses from Lev, Shire, and Dyax; expert witness fees from Lev; and grant support from Lev, Shire, and Pharming. One co-author was an employee of Lev.

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